U.S. patent application number 13/040882 was filed with the patent office on 2011-06-30 for new fused polycyclic compounds having a heterocyclic ring(s) and pharmaceutical use thereof.
This patent application is currently assigned to Ajinomoto Co., Inc.. Invention is credited to Toshihiro Hatanaka, Ryusuke HIRAMA, Takao Ikenoue, Nobuo Kondo, Yoko Masuzawa, Wataru Miyanaga, Seiji Niwa, Masaru Takayanagi, Hideyuki Tanaka, Akiyo Yamazaki.
Application Number | 20110160191 13/040882 |
Document ID | / |
Family ID | 34544082 |
Filed Date | 2011-06-30 |
United States Patent
Application |
20110160191 |
Kind Code |
A1 |
HIRAMA; Ryusuke ; et
al. |
June 30, 2011 |
NEW FUSED POLYCYCLIC COMPOUNDS HAVING A HETEROCYCLIC RING(S) AND
PHARMACEUTICAL USE THEREOF
Abstract
The present invention provides a fused polycyclic compound of
the following formula, analogues thereof and pharmaceutically
acceptable salts thereof; and agents for increasing the
sugar-transporting capacity, hypoglycemic agents and pharmaceutical
compositions containing the above compounds. This fused polycyclic
compound has high medicinal properties and few side-effects, and a
therapeutic effect on diabetes. ##STR00001## wherein R represents
an alkoxy group, R' represents an oxazolylpropionyl group or a
thiazolylpropionyl group, and R'' represent a hydrogen atom.
Inventors: |
HIRAMA; Ryusuke;
(Kawasaki-shi, JP) ; Niwa; Seiji; (Kawasaki-shi,
JP) ; Tanaka; Hideyuki; (Kawasaki-shi, JP) ;
Hatanaka; Toshihiro; (Kawasaki-shi, JP) ; Masuzawa;
Yoko; (Kawasaki-shi, JP) ; Yamazaki; Akiyo;
(Kawasaki-shi, JP) ; Ikenoue; Takao;
(Kawasaki-shi, JP) ; Kondo; Nobuo; (Kawasaki-shi,
JP) ; Miyanaga; Wataru; (Kawasaki-shi, JP) ;
Takayanagi; Masaru; (Kawasaki-shi, JP) |
Assignee: |
Ajinomoto Co., Inc.
Tokyo
JP
|
Family ID: |
34544082 |
Appl. No.: |
13/040882 |
Filed: |
March 4, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11414499 |
May 1, 2006 |
7928101 |
|
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13040882 |
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PCT/JP2004/016217 |
Nov 1, 2004 |
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11414499 |
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Current U.S.
Class: |
514/220 ;
540/557 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
27/02 20180101; C07D 487/04 20130101; A61P 3/10 20180101; A61P 3/08
20180101; A61P 25/02 20180101; A61P 9/10 20180101; A61P 3/04
20180101; A61P 13/12 20180101 |
Class at
Publication: |
514/220 ;
540/557 |
International
Class: |
A61K 31/551 20060101
A61K031/551; C07D 487/04 20060101 C07D487/04; A61P 3/10 20060101
A61P003/10 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 31, 2003 |
JP |
2003-373270 |
Claims
1. A fused polycyclic compound of the following formula (I) or a
pharmaceutically acceptable salt thereof: ##STR00084## wherein A
represents a benzene group; B represents an aromatic ring which may
have a substituent(s), a heterocyclic ring which may have a
substituent(s) or an aliphatic ring which may have a
substituent(s); C represents a heterocyclic group which may have a
substituent(s); T represents an alkylene group having 1 to 7 carbon
atoms which may have a substituent(s) wherein two carbon atoms in
the group may have a double bond or triple bond, and a part of
carbon atoms in the group may be substituted with --O--, --S--, or
--NH--; R.sup.1, R.sup.2 and R.sup.3 may be same or different from
each other and each independently represent a hydrogen atom, a
halogen atom, a hydroxyl group, an alkyl group, a mercapto group,
an alkoxy group, an alkylthio group, an alkylsulfonyl group, an
acyl group, an acyloxy group, an amino group, an alkylamino group,
a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a
nitro group, a cyano group, a trifluoromethyl group, an alkenyl
group which may have a substituent(s), an alkynyl group which may
have a substituent(s), an aryl group which may have a
substituent(s), a heteroaryl group which may have a substituent(s),
a benzyloxy group which may have a substituent(s), an aryloxy group
which may have a substituent(s), a heteroaryloxy group which may
have a substituent(s), an arylamino group which may have a
substituent(s), an arylvinyl group which may have a substituent(s)
or an arylethynyl group which may have a substituent(s); --X-- and
--Z-- may be same or different from each other and each
independently represent --O--, --NH--, --NR.sup.6--, --S--, --SO--,
--SO.sub.2--, --CH.sub.2--, --CR.sup.4R.sup.5-- or --CO--, where
R.sup.6 represents a lower alkyl group which may have a
substituent(s), an acyl group which may have a substituent(s), an
alkoxycarbonyl group which may have a substituent(s), a carbamoyl
group which may have a substituent(s) or a sulfonyl group which may
have a substituent(s), R.sup.4 and R.sup.5 may be same or different
from each other and each independently represent a hydrogen atom, a
halogen atom, a hydroxyl group, an alkyl group, a mercapto group,
an alkoxy group, an alkylthio group, an alkylsulfonyl group, an
acyl group, an acyloxy group, an amino group, an alkylamino group,
a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a
nitro group, a cyano group or a trifluoromethyl group; --W--
represents --NR.sup.9--, --O-- or --CR.sup.7R.sup.8--, wherein
R.sup.9 represents a hydrogen atom, a lower alkyl group which may
have a substituent(s) or an aryl group which may have a
substituent(s), R.sup.7 and R.sup.8 may be same or different from
each other and each independently represent a hydrogen atom, a
halogen atom, a hydroxyl group, an alkyl group, a mercapto group,
an alkoxy group, an alkylthio group, an alkylsulfonyl group, an
acyl group, an acyloxy group, an amino group, an alkylamino group,
a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a
nitro group, a cyano group or a trifluoromethyl group; --Y--
represents a nitrogen atom or --CH--; and a, b and c represents a
position of a carbon atom, respectively; with the proviso that i)
the above substituent(s) is selected from the group consisting of a
halogen atom, a hydroxyl group, an alkyl group, a mercapto group,
an alkoxy group, an alkylthio group, an alkylsulfonyl group, an
acyl group, an acyloxy group, an amino group, an alkylamino group,
a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a
nitro group, a cyano group, a trifluoromethyl group, an aryl group
and a heteroaryl group; and ii) when X is --CH.sub.2-- or
--CR.sup.4R.sup.5--, Y is a nitrogen atom.
2. The fused polycyclic compound or a pharmaceutically acceptable
salt thereof according to claim 1, wherein B is an aliphatic ring
which may have a substituent(s); C is a heterocyclic group which
may have a substituent(s); --X-- is --NH-- or --NR.sup.6--, --Y--
is a nitrogen atom; --Z-- is --CH.sub.2-- or --CR.sup.4R.sup.5--;
--W-- is --NR.sup.9--; and -T- is --CR.sup.11R.sup.12--,
--CR.sup.13R.sup.14--CR.sup.15R.sup.16-- or
--CR.sup.17.dbd.CR.sup.18--, wherein R.sup.11 to R.sup.18 each
independently represent a hydrogen atom, a halogen atom, a hydroxyl
group, an alkyl group, a mercapto group, an alkoxy group, an
alkylthio group, an alkylsulfonyl group, an acyl group, an acyloxy
group, an amino group, an alkylamino group, a carboxyl group, an
alkoxycarbonyl group, a carbamoyl group, a nitro group, a cyano
group, or a trifluoromethyl group.
3. The fused polycyclic compound or a pharmaceutically acceptable
salt thereof according to claim 2, wherein the heterocyclic group
which may have a substituent(s) represented by C is a heteroaryl
group which may have a substituent(s).
4. The fused polycyclic compound, or a pharmaceutically acceptable
salt thereof, according to claim 1, wherein the fused polycyclic
compound has the formula of: ##STR00085##
5. The fused polycyclic compound, or a pharmaceutically acceptable
salt thereof, according to claim 1, wherein the fused polycyclic
compound has the formula of: ##STR00086##
6. The fused polycyclic compound, or a pharmaceutically acceptable
salt thereof, according to claim 1, wherein the fused polycyclic
compound has the formula of: ##STR00087##
7. The fused polycyclic compound, or a pharmaceutically acceptable
salt thereof, according to claim 1, wherein the fused polycyclic
compound has the formula of: ##STR00088##
8. The fused polycyclic compound, or a pharmaceutically acceptable
salt thereof, according to claim 1, wherein the fused polycyclic
compound has the formula of: ##STR00089##
9. A method for increasing the sugar-transporting capacity in a
subject in need thereof comprising administering an effective
amount of the fused polycyclic compound or a pharmaceutically
acceptable salt thereof according to claim 1.
10. A method for treating hypoglycemia in a subject in need thereof
comprising administering an effective amount of the fused
polycyclic compound or a pharmaceutically acceptable salt thereof
according to claim 1.
11. A method for treating diabetes, diabetic peripheral neuropathy,
diabetic nephropathy, diabetic retinopathy, diabetic
macroangiopathy, impaired glucose tolerance, or obesity in a
subject in need thereof comprising administering an effective
amount of the fused polycyclic compound or a pharmaceutically
acceptable salt thereof according to claim 1.
12. A pharmaceutical composition which comprises the fused
polycyclic compound or a pharmaceutically acceptable salt thereof
according to claim 1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional of U.S. Ser. No.
11/414,499, filed on May 1, 2006, which is a continuation of
PCT/JP04/16217, filed on Nov. 1, 2004, which claims priority to JP
2003-373270, filed on Oct. 31, 2003.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to new fused polycyclic
compounds and drugs for treating diabetes which have the compounds
as an active ingredient.
BACKGROUND OF THE INVENTION
[0003] Drug therapy of Type II diabetes is positioned as a
treatment for patients whose conditions are not sufficiently
improved by dietary therapy or exercise therapy. Up to now, agents
have been developed such as preparations with insulin that is an
endogenous hormone controlling hypoglycemic actions, or oral
hypoglycemic agents having actions such as insulin secretagogue
action or peripheral insulin sensitizing action. At present, it is
the mainstream method of drug therapy of Type II diabetes that
blood glucose is precisely controlled by using oral hypoglycemic
agents. However, in case that sufficient insulin actions cannot be
obtained to improve hyperglycemia by using such agents, insulin
therapy is applied as a main method. On the other hand, to Type I
diabetes, administration of insulin therapy is the only treatment
because such patients' insulin secretion ability is extinct.
[0004] Thus, though the insulin therapy is used as an important
treatment method, there are problems such as procedure complication
and need of patient education because it is injection solutions.
Accordingly, improvement in the administration method is strongly
desired from the aspect of improvement in compliance. Recent years,
several insulin administration methods by various non-injection
preparations to replace injection solutions have been developed and
tried, but they are not led to practical use because of the
problems such as the poor absorption efficiency and unstable
absorption thereof.
[0005] As one of the main hypoglycemic actions of insulin, insulin
has the action which increases the sugar-transporting capacity of
peripheral cells, makes sugars in the blood take in the peripheral
cells, and, as a result, lowers the blood glucose level. Thus, if
new oral medicaments are found such as those lowering the blood
glucose level by an effect of increasing the sugar-transporting
capacity of peripheral cells, it is expected to become a promising
treatment for diabetic diseases. For example, the compounds
described in Patent Literature 1 are known.
[0006] [Patent Literature 1] WO 02/44180
DISCLOSURE OF THE INVENTION
[0007] The object of the present invention is to develop and
provide a drug for treating diabetes which has high medicinal
properties and few side-effects.
[0008] The further object of the present invention is to provide an
agent having an effect of increasing the sugar-transporting
capacity.
[0009] The additional object of the present invention is to provide
a hypoglycemic agent.
[0010] The further additional object of the present invention is to
provide a drug for preventing and/or treating diabetes, diabetic
peripheral neuropathy, diabetic nephropathy, diabetic retinopathy,
diabetic macroangiopathy, impaired glucose tolerance or
obesity.
[0011] The further additional object of the present invention is to
provide a new fused polycyclic compound having a heterocyclic
ring(s).
[0012] The further additional object of the present invention is to
provide a pharmaceutical composition.
[0013] The inventors thoroughly examined compounds useful as drugs
for treating diabetes, which have a strong effect of increasing the
sugar-transporting capacity, and found that specific fused
polycyclic compounds have such effects. The present invention has
been completed based of this finding.
[0014] Namely, the present invention provides the following
inventions. [0015] (1) A fused polycyclic compound of the following
formula (I) or pharmaceutically acceptable salts thereof:
##STR00002##
[0015] wherein A represents an aromatic cyclic group, a
heterocyclic group or an aliphatic cyclic group; B represents an
aromatic ring which may have a substituent(s), a heterocyclic ring
which may have a substituent(s) or an aliphatic ring which may have
a substituent(s); C represents a heterocyclic group which may have
a substituent(s); T represents an alkylene group having 1 to 7
carbon atoms which may have a substituent(s) wherein two carbon
atoms in the group may have a double bond or triple bond, and a
part of carbon atoms in the group may be substituted with --O--,
--S--, or --NH--; R.sup.1, R.sup.2 and R.sup.3 may be same or
different from each other and each independently represent a
hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, a
mercapto group, an alkoxy group, an alkylthio group, an
alkylsulfonyl group, an acyl group, an acyloxy group, an amino
group, an alkylamino group, a carboxyl group, an alkoxycarbonyl
group, a carbamoyl group, a nitro group, a cyano group, a
trifluoromethyl group, an alkenyl group which may have a
substituent(s), an alkynyl group which may have a substituent(s),
an aryl group which may have a substituent(s), a heteroaryl group
which may have a substituent(s), a benzyloxy group which may have a
substituent(s), an aryloxy group which may have a substituent(s), a
heteroaryloxy group which may have a substituent(s), an arylamino
group which may have a substituent(s), an arylvinyl group which may
have a substituent(s) or an arylethynyl group which may have a
substituent(s); --X-- and --Z-- may be same or different from each
other and each independently represent --O--, --NH--, --NR.sup.6--,
--S--, --SO--, --SO.sub.2--, --CH.sub.2--, --CR.sup.4R.sup.5-- or
--CO--, wherein R.sup.6 represents a lower alkyl group which may
have a substituent(s), an acyl group which may have a
substituent(s), an alkoxycarbonyl group which may have a
substituent(s), a carbamoyl group which may have a substituent(s)
or a sulfonyl group which may have a substituent(s), R.sup.4 and
R.sup.5 may be same or different from each other and each
independently represent a hydrogen atom, a halogen atom, a hydroxyl
group, an alkyl group, a mercapto group, an alkoxy group, an
alkylthio group, an alkylsulfonyl group, an acyl group, an acyloxy
group, an amino group, an alkylamino group, a carboxyl group, an
alkoxycarbonyl group, a carbamoyl group, a nitro group, a cyano
group or a trifluoromethyl group; --W-- represents --NR.sup.9--,
--O-- or --CR.sup.7R.sup.8--, wherein R.sup.9 represents a hydrogen
atom, a lower alkyl group which may have a substituent(s) or an
aryl group which may have a substituent(s), R.sup.7 and R.sup.8 may
be same or different from each other and each independently
represent a hydrogen atom, a halogen atom, a hydroxyl group, an
alkyl group, a mercapto group, an alkoxy group, an alkylthio group,
an alkylsulfonyl group, an acyl group, an acyloxy group, an amino
group, an alkylamino group, a carboxyl group, an alkoxycarbonyl
group, a carbamoyl group, a nitro group, a cyano group or a
trifluoromethyl group; --Y-- represents a nitrogen atom or --CH--;
and a, b and c represents a position of a carbon atom,
respectively; with the proviso that i) the above substituent(s) is
selected from the group consisting of a halogen atom, a hydroxyl
group, an alkyl group, a mercapto group, an alkoxy group, an
alkylthio group, an alkylsulfonyl group, an acyl group, an acyloxy
group, an amino group, an alkylamino group, a carboxyl group, an
alkoxycarbonyl group, a carbamoyl group, a nitro group, a cyano
group, a trifluoromethyl group, an aryl group and a heteroaryl
group; and ii) when X is --CH.sub.2-- or --CR.sup.4R.sup.5--, Y is
a nitrogen atom. [0016] (2) The fused polycyclic compound or
pharmaceutically acceptable salts thereof according to above (1),
wherein B is an aliphatic ring which may have a substituent(s); C
is a heterocyclic group which may have a substituent(s); --X-- is
--NH-- or --NR.sup.6--, --Y-- is a nitrogen atom; --Z-- is
--CH.sub.2-- or --CR.sup.4R.sup.5--; --W-- is --NR.sup.9--; and -T-
is --CR.sup.11R.sup.12--, --CR.sup.13R.sup.14--CR.sup.15R.sup.16--
or --CR.sup.17.dbd.CR.sup.18--, wherein R.sup.11 to R.sup.18 each
independently represent a hydrogen atom, a halogen atom, a hydroxyl
group, an alkyl group, a mercapto group, an alkoxy group, an
alkylthio group, an alkylsulfonyl group, an acyl group, an acyloxy
group, an amino group, an alkylamino group, a carboxyl group, an
alkoxycarbonyl group, a carbamoyl group, a nitro group, a cyano
group, or a trifluoromethyl group. [0017] (3) The fused polycyclic
compound or pharmaceutically acceptable salts thereof according to
above (2), wherein the heterocyclic group which may have a
substituent(s) represented by C is a heteroaryl group which may
have a substituent(s). [0018] (4) The fused polycyclic compound or
pharmaceutically acceptable salts thereof according to above (2),
wherein A is a phenyl group; and the heteroaryl group represented
by C is a furyl group which may have a substituent(s), a thienyl
group which may have a substituent(s), an oxazolyl group which may
have a substituent(s), an isoxazolyl group which may have a
substituent(s), a thiazolyl group which may have a substituent(s),
an oxadiazolyl group which may have a substituent(s), a
thiadiazolyl group which may have a substituent(s), a pyridyl group
which may have a substituent(s), a pyridonyl group which may have a
substituent(s), a pyridazinyl group which may have a
substituent(s), a pyrimidinyl group which may have a
substituent(s), an imidazolyl group which may have a
substituent(s), or 4-oxothiazolidine-2-thionyl group which may have
a substituent(s). [0019] (5) The fused polycyclic compound or
pharmaceutically acceptable salts thereof according to above (4),
wherein B is a cyclohexane ring which may have a substituent(s).
[0020] (6) The fused polycyclic compound or pharmaceutically
acceptable salts thereof according to above (5), wherein, in the
formula (I), --X-- is --NH-- or --NMe-; --Y--is a nitrogen atom;
--Z-- is --CH.sub.2--; --W-- is --NH--; A is a benzene ring; B is a
cyclohexane ring which may have a substituent(s); C is an oxazolyl
group which may have a substituent(s), a thiazolyl group which may
have a substituent(s), or a pyridinyl group which may have a
substituent(s); and -T- is --CR.sup.11R.sup.12--,
--CR.sup.13R.sup.14--CR.sup.15R.sup.16-- or
--CR.sup.17.dbd.CR.sup.18--, wherein R.sup.11 to R.sup.18 each
independently represent a hydrogen atom, a halogen atom, a hydroxyl
group, an alkyl group, a mercapto group, an alkoxy group, an
alkylthio group, an alkylsulfonyl group, an acyl group, an acyloxy
group, an amino group, an alkylamino group, a carboxyl group, an
alkoxycarbonyl group, a carbamoyl group, a nitro group, a cyano
group, or a trifluoromethyl group. [0021] (7) The fused polycyclic
compound or pharmaceutically acceptable salts thereof according to
above (2), wherein, in the formula (I), --X-- is --NH-- or --NMe-;
--Y-- is a nitrogen atom; --Z-- is --CH.sub.2-- or
--CR.sup.4R.sup.5--; --W-- is --NH--; A is a heterocyclic group; B
is a cyclohexane ring which may have a substituent(s); C is an
oxazolyl group which may have a substituent(s), a thiazolyl group
which may have a substituent(s), or a pyridinyl group which may
have a substituent(s); and -T- is --CR.sup.11R.sup.12--,
--CR.sup.13R.sup.14--CR.sup.15R.sup.16-- or
--CR.sup.17.dbd.CR.sup.18--, wherein R.sup.11 to R.sup.18 each
independently represent a hydrogen atom, a halogen atom, a hydroxyl
group, an alkyl group, a mercapto group, an alkoxy group, an
alkylthio group, an alkylsulfonyl group, an acyl group, an acyloxy
group, an amino group, an alkylamino group, a carboxyl group, an
alkoxycarbonyl group, a carbamoyl group, a nitro group, a cyano
group, or a trifluoromethyl group. [0022] (8) The fused polycyclic
compound or pharmaceutically acceptable salts thereof according to
above (7), wherein, in the formula (I), --Z-- is --CH.sub.2--; and
A is a heteroaryl group. [0023] (9) The fused polycyclic compound
or pharmaceutically acceptable salts thereof according to above
(6), wherein at least one of R.sup.1, R.sup.2, and R.sup.3 is --H,
--F, -Me, --OMe, --OEt, --SMe, or --OCF.sub.3, and the rest(s) is
--H. [0024] (10) The fused polycyclic compound or pharmaceutically
acceptable salts thereof according to any one of above (6) to (8),
wherein the absolute configurations of carbon atoms in a, b, and c
of the formula (I) are each independently R or S. [0025] (11) The
fused polycyclic compound or pharmaceutically acceptable salts
thereof according to above (10), wherein the absolute
configurations of carbon atoms in a and b of the formula (I) are R
together, and that of a carbon atom in c is R or S. [0026] (12) The
fused polycyclic compound or pharmaceutically acceptable salts
thereof according to above (10), wherein the absolute
configurations of carbon atoms in a and b of the formula (I) are S
together, and that of a carbon atom in c is R or S. Further, the
present invention provides the following inventions. [0027] (13) An
agent for increasing the sugar-transporting capacity, which
comprises the fused polycyclic compound or pharmaceutically
acceptable salts thereof according to above (1) as an active
ingredient. [0028] (14) A hypoglycemic agent; an agent for
preventing and/or treating diabetes, diabetic peripheral
neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic
macroangiopathy, impaired glucose tolerance, or obesity; or a
pharmaceutical composition comprising the fused polycyclic compound
or pharmaceutically acceptable salts thereof according to above (1)
as an active ingredient.
BEST MODE FOR CARRYING OUT THE INVENTION
[0029] The reinforcing effect of the sugar transportation in the
present invention indicates the action which increases the
sugar-transporting capacity via biological membranes. It may act on
the sugar transportation from outside to inside of the biological
membranes or that from inside to outside of the biological
membranes. More concretely, for example, there is an insulin
action, that is, the effect of increasing the glucose-transporting
in and to adipose cells and muscle cells.
[0030] Sugars in the sugar transportation indicates pentoses or
hexoses exist in vivo. Examples thereof include glucose, mannose,
arabinose, galactose, and fructose. Glucose is preferable among
them.
[0031] A lower alkyl group represents a linear- or branched-chain
or cyclic alkyl group having 1 to 6 carbon atoms. For example, it
includes a methyl group, ethyl group, n-propyl group, n-butyl
group, n-pentyl group, n-hexyl group, an isopropyl group, isobutyl
group, sec-butyl group, tert-butyl group, isopentyl group,
tert-pentyl group, neopentyl group, 2-pentyl group, 3-pentyl group,
n-hexyl group, 2-hexyl group, cyclopropyl group, cyclobutyl group,
cyclopentyl group and cyclohexyl group. A methyl group and ethyl
group are preferable among them.
[0032] An aryl group represents a mono- or bi-cyclic aromatic
substituent(s) composed of 5 to 12 carbon atoms. Examples thereof
are a phenyl group, indenyl group, naphthyl group and fluorenyl
group, and a phenyl group is preferable among them.
[0033] A halogen atom includes a fluorine atom, chlorine atom,
bromine atom and iodine atom.
[0034] An alkyl group represents a linear- or branched-chain or
cyclic alkyl group having 1 to 18 carbon atoms. For example, it
includes a methyl group, ethyl group, n-propyl group, n-butyl
group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl
group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl
group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl
group, isopentyl group, tert-pentyl group, neopentyl group,
2-pentyl group, 3-pentyl group, n-hexyl group, 2-hexyl group,
tert-octyl group, cyclopropyl group, cyclobutyl group, cyclopentyl
group, cyclohexyl group and 1-adamantyl group. An n-hexyl group,
n-heptyl group, n-octyl group, n-nonyl group, n-decyl group,
n-undecyl group, n-dodecyl group, isopropyl group, isobutyl group,
sec-butyl group, tert-butyl group, isopentyl group, tert-pentyl
group, neopentyl group, 2-pentyl group, 3-pentyl group, n-hexyl
group, 2-hexyl group, tert-octyl group, cyclopropyl group,
cyclobutyl group, cyclopentyl group, cyclohexyl group, 1-adamantyl
group and the like are preferable, and an isopropyl group,
tert-butyl group, tert-octyl group, 1-adamantyl group and the like
are more preferable among them.
[0035] An alkoxy group represents an alkoxy group which has a
linear- or branched-chain or cyclic alkyl group having 1 to 18
carbon atoms. For example, it includes a methoxy group, ethoxy
group, n-propoxy group, n-butoxy group, n-pentyloxy group,
n-hexyloxy group, n-heptyloxy group, n-octyloxy group, n-nonyloxy
group, n-decyloxy group, n-undecyloxy group, n-dodecyloxy group,
isopropoxy group, isobutoxy group, sec-butoxy group, tert-butoxy
group, cyclopropyloxy group, cyclobutoxy group, cyclopentyloxy
group, cyclohexyloxy group, cycloheptyloxy group,
2-cyclohexylethoxy group, 1-adamantyloxy group, 2-adamantyloxy
group, 1-adamantylmethyloxy group, 2-(1-adamantyl)ethyloxy group
and trifluoromethoxy group. Among them, a methoxy group, ethoxy
group, n-propoxy group, isopropoxy group, n-butoxy group,
tert-butoxy group, n-pentyloxy group and n-hexyloxy group are
preferable.
[0036] An alkylthio group represents an alkylthio group which has a
linear- or branched-chain or cyclic alkyl group having 1 to 12
carbon atoms. For example, it includes a methylthio group,
ethylthio group, n-propylthio group, isopropylthio group,
n-butylthio group, isobutylthio group, sec-butylthio group,
tert-butylthio group, cyclopropylthio group, cyclobutylthio group,
cyclopentylthio group and cyclobutylthio group.
[0037] An alkylsulfonyl group represents an alkylsulfonyl group
which has a linear- or branched-chain or cyclic alkyl group having
1 to 12 carbon atoms. For example, it includes a methanesulfonyl
group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl
group, pentanesulfonyl group, hexanesulfonyl group, heptanesulfonyl
group, octanesulfonyl group, nonanesulfonyl group, decanesulfonyl
group, undecanesulfonyl group and dodecanesulfonyl group.
[0038] An acyl group represents a formyl group, an acyl group which
has a linear or branched-chain or cyclic alkyl group having 1 to 6
carbon atoms, an acyl group which has a linear- or branched-chain
or cyclic alkenyl group having 1 to 6 carbon atoms, an acyl group
which has a linear- or branched-chain or cyclic alkynyl group
having 1 to 6 carbon atoms, or an acyl group which has an aryl
group that may be substituted. Examples thereof are a formyl group,
acetyl group, propionyl group, butyryl group, isobutyryl group,
valeryl group, isovaleryl group, pivaloyl group, hexanoyl group,
acryloyl group, metacryloyl group, crotonoyl group, isocrotonoyl
group, benzoyl group and naphthoyl group.
[0039] An acyloxy group represents a formyloxy group, an acyloxy
group which has a linear- or branched-chain or cyclic alkyl group
having 1 to 6 carbon atoms, or an acyloxy group which has an aryl
group that may be substituted. For example, it includes a formyloxy
group, acetyloxy group, propionyloxy group, butyryloxy group,
isobutyryloxy group, valeryloxy group, isovaleryloxy group,
pivaloyloxy group, hexanoyloxy group, acryloyloxy group,
metacryloyloxy group, crotonoyloxy group, isocrotonoyloxy group,
benzoyloxy group and naphthoyloxy group.
[0040] An alkylamino group represents an amino group which is
monosubstituted or disubstituted with an alkyl group(s), and
examples of the alkyl group(s) are the same as those mentioned in
the above "alkyl group." Concretely, they include a methylamino
group, ethylamino group, propylamino group, isopropylamino group,
dimethylamino group, diethylamino group, dipropylamino group,
diisopropylamino group and methylethylamino group.
[0041] An alkoxycarbonyl group represents an alkoxycarbonyl group
which has a linear- or branched-chain or cyclic alkyl group having
1 to 8 carbon atoms. Examples thereof are a methoxycarbonyl group,
ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl
group, n-butoxycarbonyl group, isobutoxycarbonyl group,
sec-butoxycarbonyl group, tert-butoxycarbonyl group and
benzyloxycarbonyl group.
[0042] A carbamoyl group represents a carbamoyl group which may
have a linear- or branched-chain or cyclic alkyl group having 1 to
6 carbon atoms on a nitrogen. For example, it includes a carbamoyl
group, N-methylcarbamoyl group, N-ethylcarbamoyl group,
N,N-dimethylcarbamoyl group, N-pyrrolidylcarbonyl group,
N-piperidylcarbonyl group and N-morpholinylcarbonyl group.
[0043] A sulfonyl group represents a sulfonyl group which may have
a linear- or branched-chain or cyclic alkyl group having 1 to 6
carbon atoms on a sulfur atom. For example, it includes a
methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group and
butylsulfonyl group.
[0044] An aromatic ring represents a monocyclic or bicyclic
aromatic ring which is composed of carbon atoms. For example, it
includes a benzene ring, naphthalene ring, indene ring and fluorene
ring, and a benzene ring and naphthalene ring are preferable.
[0045] A heterocyclic ring represents a heterocyclic ring
consisting of 1 to 3 ring(s) each comprising 5 to 7 members of
carbon and nitrogen, oxygen, sulfur or the like. For example, it
includes a pyridine ring, dihydropyran ring, pyridazine ring,
pyrimidine ring, pyrazine ring, pyrrole ring, furan ring, thiophene
ring, oxazole ring, isooxazole ring, pyrazole ring, imidazole ring,
thiazole ring, isothiazole ring, thiadiazole ring, pyrrolidine
ring, piperidine ring, piperazine ring, indole ring, isoindole
ring, benzofuran ring, isobenzofuran ring, benzothiophene ring,
benzopyrazole ring, benzoimidazole ring, benzooxazole ring,
benzothiazole ring, purine ring, pyrazolopyridine ring, quinoline
ring, isoquinoline ring, naphthyridine ring, quinazoline ring,
benzodiazepine ring, carbazole ring and dibenzofuran ring. A
pyridine ring, pyrimidine ring, pyridazine ring, pyrimidine ring,
furan ring and thiophene ring are preferable among them.
[0046] An aromatic cyclic group represents a monocyclic, bicyclic
or tricyclic aromatic hydrocarbon group which has no substituent.
For example, it includes a phenyl group, naphthalyl group,
anthracenyl group and phenanthrenyl group.
[0047] A heterocyclic group represents a heterocyclic substituent
composed of 1 to 3 ring(s) each comprising 5 to 8 members, having 1
to 4 hetero atom(s) selected from an oxygen atom(s), a sulfur
atom(s) and a nitrogen atom(s) as a cyclic atom(s), having no
substituent. Meanwhile, an arbitrary carbon atom(s) that is a
cyclic atom may be substituted with an oxo group, and a sulfur atom
or a nitrogen atom may be oxidized and form an oxide. Further, it
may be fused with a benzene ring, and the heterocyclic group may be
bridged or form a spirocycle. For example, it includes a pyridyl
group, pyridazinyl group, pyrimidyl group (=pyrimidinyl group),
pyrazinyl group, furyl group, thienyl group, pyrrolyl group,
isoxazolyl group, oxazolyl group, isothiazolyl group, thiazolyl
group, pyrazolyl group, imidazolyl group, oxadiazolyl group,
thiadiazolyl group, triazoyl group, tetrazolyl group, benzofuranyl
group, benzothienyl group, indolyl group, isoindolyl group,
benzoxazolyl group, benzothiazolyl group, benzimidazolyl group,
indazolyl group, benzisoxazolyl group, benzisothiazolyl group,
benzofurazanyl group, benzothiadiazolyl group, purinyl group,
quinolyl group (=quinolinyl group), isoquinolyl group, cynnolinyl
group, phtharazinyl group, quinazolinyl group, quinoxalinyl group,
pteridinyl group, imidazoxazolyl group, imidazothiazolyl group,
imidazoimidazolyl group, dibenzofuranyl group, dibenzothienyl
group, carbazolyl group, acridinyl group, pyrrolidinyl group,
pyrazolidinyl group, imidazolidinyl group, pyrrolinyl group,
pyrazolinyl group, imidazolinyl group, tetrahydrofuranyl group,
tetrahydrothiophenyl group, thiazolidinyl group, piperidinyl group
(=piperidyl group), piperazinyl group, quinuclidinyl group,
tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group,
dioxolanyl group, homopiperidinyl group (=homopiperidyl group),
homopiperazinyl group, indolinyl group, isoindolinyl group,
chromanyl group, isochromanyl group, 8-azabicyclo[3.2.1]octan-3-yl
group, 9-azabicyclo[3.3.1]nonan-3-yl group,
3-azabicyclo[3.2.1]octan-6-yl group,
7-azabicyclo[2.2.1]peptane-2-yl group,
2-azatricyclo[3.3.1.1]decan-4-yl group,
1-azabicyclo[2.2.2]octan-2-yl group, 1-azabicyclo[2.2.2]octan-3-yl
group, 1-azabicyclo[2.2.2]octan-4-yl group,
3-azaspiro[5.5]undecan-9-yl group, 2-azaspiro[4.5]decan-8-yl group,
2-azaspiro[4.4]nonan-7-yl group, and 8-azaspiro[4.5]decan-2-yl
group.
[0048] An aliphatic cyclic group represents a nonaromatic
hydrocarbon group having 3 to 10 carbon atoms, which has no
substituent. For example, it includes a cyclopentyl group,
cyclohexyl group, and cycloheptyl group.
[0049] An aliphatic ring represents a monocyclic or bicyclic
aliphatic ring which is composed of carbon atoms. For example, it
includes a cyclopropane ring, cyclobutane ring, cyclopentane ring,
cyclohexane ring, cycloheptane ring, cyclooctane ring, decalin ring
and norbornane ring, and cylohexane ring is preferable.
[0050] An heteroaryl group represents an aromatic heterocyclic
group consisting of 1 to 3 ring(s) each comprising 5 to 7 members
of carbon and nitrogen, oxygen, sulfur or the like. For example, it
includes a pyridyl group, pyridazinyl group, pyrimidinyl group,
pyrazinyl group, pyrrolyl group, furanyl group, thienyl group,
oxazolyl group, isoxazolyl group, pyrazolyl group, imidazolyl
group, thiazolyl group, isothiazolyl group, thiadiazolyl group,
indolyl group, isoindolyl group, benzofuryl group, isobenzofuryl
group, benzothienyl group, benzopyrazolyl group, benzoimidazolyl
group, benzoxazolyl group, benzothiazolyl group, quinolyl group,
isoquinolyl group, naphthyridinyl group and quinazolyl group. A
2-pyridyl group, 3-pyridyl group, 4-pyridyl group and 1-pyrazolyl
group are preferable among them.
[0051] An aryloxy group is an aryloxy group having an aryl group on
an oxygen atom, and examples of the aryl group are the same as
those mentioned in the above "aryl group." Concretely, it includes
a phenoxy group, 1-naphthyloxy group and 2-naphthyloxy group.
[0052] A heteroaryloxy group is a heteroaryloxy group having a
heteroaryl group on an oxygen atom, and examples of the heteroaryl
group are the same as those mentioned in the above "heteroaryl
group." Concretely, it includes a 2-pyridyloxy group, 3-pyridyloxy
group, 4-pyridyloxy group and 2-pyrimidinyl group.
[0053] An arylamino group is an arylamino group having an aryl
group(s) on a nitrogen atom and examples of the aryl group(s) are
the same as those mentioned in the above "aryl group." Concretely,
it includes a phenylamino group, 1-naphthylamino group and
2-naphthylamino group.
[0054] An arylvinyl group is a vinyl group of which the first
position or the second position is substituted with an aryl
group(s), and examples of the aryl group(s) are the same as those
mentioned in the above "aryl group." Concretely, it includes a
1-phenylvinyl group and 2-phenylvinyl group.
[0055] An arylethynyl group is an ethynyl group of which the second
position is substituted with an aryl group(s), and examples of the
aryl group(s) are the same as those mentioned in the above "aryl
group." Concretely, it includes a phenylethynyl group.
[0056] The term "which may have a substituent(s)" indicates the
case in which a group does not have any substituents and the case
in which, if a group has a substituent(s), at least one or more
thereof are substituted with the substituent(s) mentioned in the
above (I). The substituent(s) may be same or different from each
other, and the position and number thereof are optional and not
particularly limited.
[0057] Further, in the present invention, the lactam compound of
the formula (I) according to claim 1 or pharmaceutically acceptable
salts thereof are preferably those mentioned below.
[0058] R.sup.9 is preferably a hydrogen atom and a methyl
group.
[0059] R.sup.1, R.sup.2 and R.sup.3 are preferably a hydrogen atom,
a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group,
an alkylthio group, an acyl group, an acyloxy group, an amino
group, an alkoxycarbonyl group, a carbamoyl group, a nitro group, a
cyano group, a trifluoromethyl group, a trifluoromethoxy group, an
aryl group which may have a substituent(s), a heteroaryl group
which may have a substituent(s), a benzyloxy group, an aryloxy
group which may have a substituent(s) or an arylethynyl group which
may have a substituent(s). More preferable ones are a hydrogen
atom, a halogen atom, a hydroxyl group, a methyl group, an ethyl
group, a propyl group, an isopropyl group, a methoxy group, an
ethoxy group, a methylthio group, an ethylthio group, n-propoxy
group, an isopropoxy group, a trifluoromethyl group and a
trifluoromethoxy group.
[0060] --X-- is preferably --NH--, --NR.sup.6-- wherein R.sup.6
represents a lower alkyl group, --O--, --S-- or --CH.sub.2--.
--NH-- or --NMe- is more preferable among them.
[0061] --Y-- is preferably a nitrogen atom.
[0062] --Z-- is preferably --NH-- or --CR.sup.4R.sup.5-- wherein
R.sup.4 and R.sup.5 may be same or different from each other and
each independently represent a hydrogen atom or a lower alkyl group
which may have a substituent(s), and --CH.sub.2-- is more
preferable.
[0063] --W-- is preferably --NH--, --NR.sup.9-- wherein R.sup.9
represents a lower alkyl group, or --CH.sub.2--, and --NH-- or
--NMe- is more preferable.
[0064] A is preferably an aromatic cyclic group or a heterocyclic
group. A phenyl group, a pyridyl group, a pyrimidinyl group, a
thienyl group, a benzothienyl group, an indolyl group, a quinolyl
group and a benzothiazolyl group are more preferable among them,
and a phenyl group, a thienyl group, a benzothienyl group, an
indolyl group, a quinolyl group and a benzothiazolyl group are
further more preferable, and a phenyl group is particularly
preferable among them.
[0065] B is preferably an aromatic ring which may have a
substituent(s) or an aliphatic ring which may have a
substituent(s). A benzene ring which may have a substituent(s) or a
cyclohexane ring which may have a substituent(s) is more preferable
among them, and a cyclohexane ring which may have a substituent(s)
is further more preferable.
[0066] When B is a cyclohexane ring which may have a
substituent(s), the absolute position of a carbon atom in a and b
is preferably R or S, and R is further more preferable.
[0067] C is preferably a furyl group which may have a
substituent(s), a thienyl group which may have a substituent(s), an
oxazolyl group which may have a substituent(s), an isoxazolyl group
which may have a substituent(s), a thiazolyl group which may have a
substituent(s), an oxadiazolyl group which may have a
substituent(s), a thiadiazolyl group which may have a
substituent(s), a pyridinyl group which may have a substituent(s),
a pyridonyl group which may have a substituent(s), a pyridazinyl
group which may have a substituent(s), a pyrimidinyl group which
may have a substituent(s), an imidazolyl group which may have a
substituent(s), or 4-oxothiazolidine-2-thionyl group which may have
a substituent(s). Particularly, an oxazolyl group which may have a
substituent(s), a thiazolyl group which may have a substituent(s),
and a pyridinyl group which may have a substituent(s) are more
preferable.
[0068] T is preferably a bond consisting of one or two atom(s).
--CH.sub.2--, --CR.sup.11R.sup.12--,
--CR.sup.13R.sup.14--CR.sup.15R.sup.16-- and
--CR.sup.17.dbd.CR.sup.18-- wherein R.sup.11 to R.sup.18 each
independently represent a hydrogen atom, a halogen atom, a hydroxyl
group, an alkyl group, a mercapto group, an alkoxy group, an
alkylthio group, an alkylsulfonyl group, an acyl group, an acyloxy
group, an amino group, an alkylamino group, a carboxyl group, an
alkoxycarbonyl group, a carbamoyl group, a nitro group, a cyano
group, or a trifluoromethyl group are more preferable, and
--CH.sub.2--, --CH.sub.2--CH.sub.2-- and --CH.dbd.CH-- are
particularly more preferable among them.
[0069] The pharmaceutically acceptable salts include, for example,
in the case of the compounds of the present invention, which are
sufficiently acidic, ammonium salts thereof, alkali metal salts
(such as sodium salts and potassium salts, as preferable examples),
alkaline earth metal salts (such as calcium salts and magnesium
salts, as preferable examples); as salts of an organic base, for
example, dicyclohexylamine salts, benzathine salts,
N-methyl-D-glucan salts, hydramine salts, and salts of amino acids
such as arginine and lysine. Further, in the case of the compounds
of the present invention, which are sufficiently basic, the salts
include acid addition salts thereof, such as those with inorganic
acids, e. g. hydrochloric acid, sulfuric acid, nitric acid and
phosphoric acid; or those with organic acids, e. g. acetic acid,
lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid
and monomethyl sulfate. In some cases, they may be wet salts or
hydrates.
[0070] The present invention includes all isomers such as optical
isomers and geometric isomers, hydrates, solvates or crystal
forms.
[0071] The compound of the present invention can be synthesized by
using or applying the method described in WO02/44180.
[0072] For example, in the compound (I) of the present invention, a
compound (IV) wherein X and W are --NH--; Z is --CH.sub.2--; Y is a
nitrogen atom; A is a benzene ring; and B is a cyclohexane ring can
be synthesized as mentioned below in accordance with the method
described in WO02/44180, by condensing a compound (II) described in
WO02/44180 and a carboxylic acid (III) that can be synthesized by
using known methods or applying them.
##STR00003##
wherein R represents a substituent on a benzene ring.
[0073] Further, a compound (VI) wherein, in the above compound
(IV), T is --CH.sub.2-- and C is a thiazole that may have a
substituent(s) can be synthesized by leading an ester part of a
compound (V) that is obtained by condensation of the compound (II)
with a malonic monoester to a thiazole ring in accordance with the
publicly known methods.
##STR00004##
wherein R represents a substituent on a benzene ring, and R'
represents a substituent on a thiazole ring.
[0074] Additionally, a compound (VIII) wherein, in the above
compound (IV), T is --CH.sub.2--CH.sub.2-- and C is an oxadiazole
or a thiadiazole that may have a substituent(s) can be synthesized
by leading an ester part of a compound (VII) that is obtained by
condensation of the compound (II) with a succinic monoester to an
oxadiazole ring or a thiadiazole ring in accordance with the
publicly known methods.
##STR00005##
wherein each of R and R' represents a substituent on each rings,
and U represents a oxygen atom or a sulfur atom.
[0075] Further, a compound (X) wherein, in the above compound (IV),
T is --CH.sub.2-- and C is a pyridone that may have a
substituent(s) can be synthesized by the substitution reaction of a
chloro group(s) to a compound (IX) that is obtained by condensation
of the compound (II) with a chloroacetic anhydride.
##STR00006##
wherein each of R and R' represents a substituent on each
rings.
[0076] The compounds of the present invention other than those
mentioned above can also be synthesized by applying the above
reactions.
[0077] Meanwhile, the compounds of the present invention obtained
by the above methods can be purified with methods usually used in
organic syntheses, such as extraction, distillation,
crystallization and column chromatography.
[0078] The obtained compounds of the present invention have an
effect of increasing the sugar-transporting capacity as mentioned
below, and are useful for treating patients, taking advantage of
this action. Namely, since an effect of increasing the
sugar-transporting capacity lowers the blood glucose level, the
compounds of the present invention are useful as drugs preventing
and/or treating diabetes, diabetic peripheral neuropathy, diabetic
nephropathy, diabetic retinopathy, diabetic macroangiopathy,
impaired glucose tolerance or obesity.
[0079] When using the compounds of the present invention as the
drugs preventing and/or treating diabetes, diabetic peripheral
neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic
macroangiopathy, impaired glucose tolerance or obesity, they can be
administered orally, intravenously, or transdermally. Though the
dosage differs depending on a patient's symptom, age and
administration method, it is usually 0.001 to 1000 mg/kg/day.
[0080] The compounds of the present invention can be formulated
into a pharmaceutical preparation by ordinary methods. The dosage
forms are, for example, injection solvents, tablets, granules,
subtle granules, powders, capsules, cream pharmaceuticals and
suppositories. The preparation carriers include such as lactose,
glucose, D-mannitol, starch, crystalline cellulose, calcium
carbonate, kaolin, starch, gelatin, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, polyvinylpyrrolidone, ethanol,
carboxy methyl cellulose, carboxy methyl cellulose calcium salts,
magnesium stearate, talc, acetyl cellulose, sucrose, titanium
oxide, benzoic acid, p-hydroxybenzoate ester, sodium
dehydroacetate, gum arabic, tragacanth, methyl cellulose, egg yolk,
surfactants, sucrose, simple syrup, citric acid, distilled water,
ethanol, glycerin, propylene glycols, macrogol, monobasic sodium
phosphate, dibasic sodium phosphate, sodium phosphate, glucose,
sodium chloride, phenol, thimerosal, p-hydroxybenzoate ester and
acid sodium sulfite. They are used by being mixed with the
compounds of the present invention depending on the dosage
forms.
[0081] Further, the content of the active ingredient of the present
invention in the preparation of the present invention significantly
varies depending on the dosage forms and is not particularly
limited. Generally, the content is about 0.01 to 100 wt %, and
preferably 1 to 100 wt % to a total amount of compositions.
[0082] The compounds of the present invention have an effect of
increasing the sugar-transporting capacity, and are useful for
treating the diabetic diseases. Namely, since an effect of
increasing the sugar-transporting capacity lowers the blood
glucose, the compounds of the present invention are useful as drugs
preventing and/or treating diabetes, diabetic peripheral
neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic
macroangiopathy, impaired glucose tolerance or obesity.
EXAMPLES
[0083] Next, Examples will further illustrate the present
invention. They only explain the present invention and do not
particularly limit the invention.
Examples 1 to 55
[0084] The Compounds 1 to 47 described in the following Table 1 and
the Compounds 48 to 55 described in Table 1-2 were synthesized in
accordance with the method described in WO02/44180. [0085] In this
regard, the symbols in Tables are as follows: No.: Example/Compound
No., R: a substituent on a benzene ring, R': an acyl group, R'': an
alkyl group, D: data on the compound, MS:ESI-MS m/z, N1: 1H-NMR
(DMSO-d6, TMS internal standard, .delta.ppm). The number located in
front of a substituent in R indicates the position of the
substituent on a benzene ring.
TABLE-US-00001 [0085] TABLE 1 ##STR00007## No. R R' R'' D 1 2-OMe
##STR00008## H N1: 0.50-3.40 (13H, m), 3.68 (3H, s), 3.73 (1H, J =
16.0 Hz, d), 3.81 (1H, J = 16.0 Hz, d), 3.94-4.08 (1H, m), 5.80
(1H, s), 6.65 (1H, s), 6.69 (1H, s), 6.83-7.04 (5H, m), 7.24-7.32
(2H, m) MS: 452 (M + H)+ 2 2-OMe ##STR00009## H N1: 0.50-3.40 (13H,
m), 3.74 (1H, J = 16.0 Hz, d), 3.77 (3H, s), 3.82 (1H, J = 16.0 Hz,
d), 3.90-4.07 (1H, m), 5.82 (1H, s), 6.04 (1H, J = 3.0 Hz, d),
6.30-6.34 (1H, m), 6.65 (1H, s), 6.70 (1H, s), 6.85- 7.04 (3H, m),
7.24-7.32 (1H, m), 7.47-7.51 (1H, m) MS: 436 (M + H)+, 434 (M - H)-
3 2-OMe ##STR00010## H N1: 0.51-3.38 (13H, m), 3.55-3.89 (9H, m),
3.72 (3H, s), 3.73- 3.88 (2H, m), 3.94-4.08 (1H, m), 5.83 (1H, s),
6.64 (1H, s), 6.68 (1H, s), 6.81-7.46 (7H, m)-. MS: 452 (M + H)+,
450 (M - H)-. 4 2-OMe ##STR00011## H N1: 0.50-3.40 (13H, m), 3.71
(3H, s), 3.73 (1H, J = 16.0 Hz, d), 3.80(1H, J = 16.0 Hz, d),
3.90-4.05 (1H, m), 5.81 (1H, s), 6.65 (1H, s), 6.70 (1H, s),
6.84-7.04 (3H, m), 7.23-7.33 (2H, m), 7.60- 7.69 (1H, m), 8.34-8.49
(2H, m) MS: 447 (M + H)+ 5 2-OMe ##STR00012## H N1: 0.50-3.61 (13H,
m), 3.65-4.07 (3H, m), 3.73 (3H, s), 5.82 (1H, s), 6.65 (1H, s),
6.71 (1H, s), 6.61-8.48 (8H, m)-. MS: 447 (M + H)+, 445 (M - H)-. 6
2-Me ##STR00013## H N1: 0.50-3.40 (13H, m), 2.33 (3H, s), 3.76 (1H,
J = 16.0 Hz, d), 3.86 (1H, J = 16.0 Hz, d), 3.90-4.03 (lH, m), 5.67
(1H, s), 5.98- 6.04 (1H, m), 6.28-6.34 (1H, m), 6.71 (1H, s), 6.78
(1H, s), 7.00- 7.24 (4H, m), 7.45-7.50 (1H, m) MS: 420 (M + H)+,
418 (M - H)- 7 H ##STR00014## H N1: 0.50-3.40 (13H, m), 3.76 (1H, J
= 16.0 Hz, d), 3.83 (1H, J = 16.0 Hz, d), 3.92-4.06 (1H, m), 5.70
(1H, s), 6.04-6.09 (1H, s), 6.30-6.36 (1H, m), 6.71 (1H, s), 6.78
(lH, s), 7.20-7.39 (4H, m), 7.46-7.51 (1H, m) MS: 405 (M + H)+, 404
(M - H)- 8 2-F ##STR00015## H N1: 0.50-3.40 (13H, m), 3.78 (1H, J =
16.0 Hz, d), 3.85 (1H, J = 16.0 Hz, d), 3.93-4.07 (1H, m), 5.86
(1H, s), 6.02-6.07 (1H, m), 6.29-6.35 (1H, m), 6.76-6.85 (2H, m),
7.07-7.50 (5H, m) MS: 424 (M + H)+, 422 (M - H)- 9 2-Me
##STR00016## H N1: 0.50-3.40 (13H, m), 2.28 (3H, s), 3.72 (1H, J =
16.0 Hz, d), 3.83 (1H, J = 16.0 Hz, d), 3.87-4.03 (1H, m), 5.68
(1H, s), 6.68 (1H, s), 6.75 (1H, s), 6.97-7.30 (5H, m), 7.58-7.66
(1H, m), 8.34- 8.46 (2H, m) MS: 431 (M + H)+, 429 (M - H)- 10 2-OMe
##STR00017## H N1: 0.50-2.95 (9H, m), 3.62 (1H, d, J = 15.9 Hz),
3.75 (1H, d, J = 15.9 Hz), 3.83 (3H, s), 3.95-4.05 (1H, m), 4.07
(1H, d, J = 16.2 Hz), 4.14 (1H, d, J = 16.2 Hz), 5.90 (1H, s), 6.60
(1H, s), 6.64 (1H, s), ( 6.85-7.35 (7H, m). MS: 438 (M + H)+, 436
(M - H)-. 11 2-OMe ##STR00018## H N1: 0.50-2.90 (15H, m), 3.71 (3H,
s), 3.74 (1H, d, J = 16.2 Hz), 3.82 (1H, d, J = 16.2 Hz), 3.95-4.05
(1H, m), 5.78 (1H, s), 6.64 (1H, s), 6.70 (1H, s), 6.75-7.34 (4H,
m). MS: 464 (M - H)-. 12 2-OMe ##STR00019## H N1: 0.50-2.90 (9H,
m), 2.17 (3H, s), 3.70 (1H, d, J = 16.8 Hz), 3.80 (1H, d, J = 16.2
Hz), 3.86 (3H, s), 3.90-4.00 (1H, m), 4.01 (1H, d, J = 16.2 Hz),
4.12 (1H, d, J = 16.8 Hz), 5.76 (1H, s), 6.15 (1H, s), 6.68 (1H,
s), 6.72 (1H, s), 6.87-7.40 (4H, m). MS: 435 (M - H)-. 13 2-Me
##STR00020## H N1: 0.45-2.85 (9H, m), 2.32 (3H, s), 3.62 (1H, d, J
= 16.2 Hz), 3.78 (1H, d, J = 16.2 Hz), 3.90-4.05 (1H, m), 5.80 (1H,
s), 6.65 (1H, s), 6.71 (1H, s), 6.85-7.35 (7H, m). MS: 422 (M +
H)+, 420 (M- H)-. 14 2-OMe ##STR00021## H N1: 0.50-3.40 (9H, m),
3.73 (3H, s), 3.70-3.85 (2H, m), 3.90- 4.05 (1H, m), 5.81 (1H, s),
6.67 (1H, s), 6.71 (1H, s), 6.86- 7.31 (4H, m), 7.53 (1H, d, J =
3.3 Hz), 7.67 (1H, d, J = 3.3 Hz). MS: 453 (M + H)+, 451 (M - H).-
15 2-OMe ##STR00022## H N1: 0.50-2.90 (9H, m), 3.69 (1H, d, J =
16.5 Hz), 3.79 (1H, d, J = 16.5 Hz), 3.85 (3H, s), 3.85-4.00 (2H,
m), 3.90-4.00 (2H, m), 5.53 (1H, s), 6.17 (1H, brs), 6.33 (1H,
brs), 6.62 (1H, s), 6.68 (1H, s), 6.87-7.32 (4H, m), 7.49 (1H,
brs). MS: 422 (M + H)+, 420 (M- H)-. 16 2-Me ##STR00023## H N1:
0.45-2.80 (9H, m), 2.34 (3H, s), 3.72 (1H, d, J = 16.5 Hz), 3.84
(1H, d, J = 16.5 Hz), 3.90-4.05 (1H, m), 5.72 (1H, s), 6.20 (1H, d,
J = 3.0 Hz), 6.34 (1H, dd, J = 3.0, 3.0 Hz), 6.68 (1 H, s), 6.75
(1H, s), 7.01-7.25 (4H, m), 7.50-7.51 (1H, m). MS: 404 (M - H)-. 17
2-OMe ##STR00024## H N1: 0.50-3.00 (13H, m), 2.47 (3H, s), 3.74
(3H, s), 3.74 (1H, d, J = 16.21 Hz), 3.82 (1H, d, J = 16.2 Hz),
3.90-4.05 (1H, m), 5.83 (1H, s), 6.66 (1H, s), 6.72 (1H, s),
6.85-7.31 (4H, m), 7.09-8.26 (3H, m). MS: 461 (M + H)+, 459 (M -
H)-. 18 2-OMe ##STR00025## Me N1: 0.50-3.40 (13H, m), 2.78 (3H, s),
3.77 (3H, s), 3.82 (1H, J = 16.0 Hz, d), 3.85-3.99 (1H, m), 4.08
(1H, J = 16.0 Hz, d), 5.78 (1H., s), 6.00-6.05 (1H, m), 6.30-6.35
(1H, m), 6.86-7.08 (4H, m), 7.24-7.33 (2H, m), 7.45-7.49 (1H, m)
MS: 450 (M + H)+ 19 2-Me ##STR00026## Me N1: 0.50-3.40 (13H, m),
2.31 (3H, s), 2.77 (3H, s), 3.83-3.96 (1H, m), 3.87 (1H, J = 16.0
Hz, d), 4.07 (1H, J = 16.0 Hz, d), 5.65 (1H, s), 5.96-6.00 (1H, m),
6.31-6.35 (1H, m), 7.06-7.24 (6H, m), 7.44- 7.50 (1H, m) MS: 434 (M
+ H)+ 20 2-OMe ##STR00027## H N1: 0.50-3.05 (14H, m), 3.75 (1H, d,
J = 16.5 Hz), 3.82 (1H, d, J = 16.5 Hz), 3.83 (3H, s), 3.90-4.05
(1H, m), 5.83 (1H, s), 6.65 (1H, s), 6.72 (1H, s), 6.86-7.32 (4H,
m), 7.07 (1H, s), 7.96 (1H, s). MS: 437 (M + H)+, 435 (M - H)-. 21
2-Me ##STR00028## H N1: 0.45-3.40 (13H, m), 2.37 (3H, s), 3.77 (1H,
d, J = 16.5 Hz), 3.86 (1H, d, J = 16.5 Hz), 3.90-4.00 (1H, m), 5.68
(1H, s), 6.70 (1H, s), 6.78 (1H, s), 7.03-7.21 (4H, m), 7.05 (1H,
s), 7.93 (1H, s). MS: 419 (M - H)-. 22 2-Me ##STR00029## H N1:
0.45-3.20 (13H, m), 2.33 (3H, s), 3.75 (1H, d, J = 16.5 Hz), 3.85
(1H, d, J = 16.5 Hz), 3.90-4.05 (1H, m), 5.66 (1H, s), 6.71 (1H,
s), 6.77 (1H, s), 7.00-7.24 (4H, m), 7.52 (1H, d, J = 3.3 Hz), 7.66
(1H, d, J = 3.3 Hz). MS: 434 (M - H)-. 23 2-OMe ##STR00030## H N1:
0.50-3.40 (14H, m), 2.30 (3H, s), 3.7 3(1H, d, J = 16.5 Hz), 3.75
(3H, s), 3.82 (1H, d, J = 16.5 Hz), 3.90-4.05 (1H, m), 5.81 (1H,
s), 6.66 (1H, s), 6.71 (1H, s), 6.84-7.38 (4H, m). MS: 467 (M +
H)+, 466 (M - H)-. 24 2-OMe ##STR00031## H N1: 0.86-3.18 (13H, m),
2.18 (3H, s), 3.80-3.87 (5H, m), 3.99 (1H, s), 6.10 (1H, s),
6.71-7.33 (6H, m). MS: 451 (M + H)+. 25 2-Me ##STR00032## H N1:
0.45-3.20 (13H, m), 2.34 (3H, s), 3.76 (1H, d, J = 16.8 Hz), 3.86
(1H, d, J = 16.8 Hz), 3.90-4.05 (1H, m), 5.69 (1H, s), 6.69 (1H,
s), 6.76 (1H, s), 7.00-7.26 (4H, m), 7.14-8.46 (4H, m). MS: 431 (M
+ H)+, 429 (M - H)-. 26 2-OMe ##STR00033## H N1: 0.85-3.17 (13H,
m), 2.16 (3H, s), 2.29 (3H, s), 3.69-3.84 (5H, m), 5.80 (1H, s),
6.63-7.32 (6H, m). MS: 465 (M + H)+. 27 2-OMe ##STR00034## H N1:
0.50-3.30 (13H, m), 2.37 (3H, s), 3.73 (1H, d, J = 16.5 Hz), 3.74
(3H, s), 3.82 (1H, d, J = 16.5 Hz), 3.90-4.05 (1H, m), 5.81 (1H,
s), 6.66 (1H, s), 6.71 (1H, s), 6.84-7.34 (4H, m), 7.31 (1H, d, J =
1.5 Hz). MS: 465 (M - H)-. 28 2-OMe ##STR00035## H N1: 0.55-3.05
(9H, m), 3.74 (1H, d, J = 16.5 Hz), 3.82 (1H, d, J = 16.5 Hz)(
3.90-4.05 (1H, m), 3.83 (3H, s), 4.05-4.20 (1H, m), 6.01 (1H, s),
6.73 (1H, s), 6.73 (1H, s), 6.86-7.10 (4H, m), 7.50 (1H, d, J =
16.3 Hz), 7.76 (1H, d, J = 15.6 Hz), 7.84 (1H, d, J = 3.0 Hz), 7.94
(1H, d, J = 3.0 Hz). MS: 449 (M - H)-. 29 2-Me ##STR00036## H N1:
0.50-3.00 (9H, m), 2.32 (3H, s), 3.78 (1H, d, J = 16.2 Hz), 3.87
(1H, d, J = 16.2 Hz), 4.00-4.15 (1H, m), 5.92 (1H, s), 6.80 (1H,
s), 6.80 (1H, s), 7.04-7.25 (4H, m), 7.46 (1H, d, J = 14.4 Hz),
7.61 (1H, d, J = 14.7 Hz), 7.87 (1H, d, J = 3.0 Hz), 7.95 (1H, d, J
= 3.3 Hz). MS: 432 (M - H)-. 30 2-OMe ##STR00037## H N1: 0.50-3.15
(13H, m), 2.28 (3H, s), 3.75 (1H, d, J = 15.9 Hz), 3.83 (1H, d, J =
16.9 Hz), 3.85-3.95 (1H, m), 3.85 (3H, s), 5.82 (1H, s), 6.67 (1H,
s), 6.74 (1H, s), 6.85-7.34 (4H, m). MS: 450 (M - H)-. 31 2-Me
##STR00038## H N1: 0.50-3.40 (13H, m), 2.36 (3H, s), 3.65-4.10 (3H,
m), 5.71 (1H, brs), 6.70 (1H, brs), 6.78 (1H, brs), 7.00-7.70 (6H,
m), 9.06 (1H, s) MS: 432 (M + H)+, 430 (M - H)- 32 2-OMe
##STR00039## H N1: 0.50-3.40 (9H, m), 3.70-3.90 (2H, m), 3.82 (3H,
s), 4.10- 4.20 (1H, m), 6.09 (1H, s), 6.75 (2H, s), 6.90-7.10 (3H,
m), (7.25-7.38 (2H, m), 7.45 (1H, t, J = 4.8 Hz), 8.22 (1H, d, J =
15.0 Hz), 8.87 (2H, d, J = 4.8 Hz) MS: 446 (M + H)+, 444 (M - H)-.
33 2-OMe ##STR00040## H N1: 0.50-3.40 (13H, m), 3.70-3.90 (2H, m),
3.85 (3H, s), 3.90- 4.05 (1H, m), 5.90 (1H, s), 6.65 (1H, s), 6.72
(1H, s), 6.88-7.34 (5H, m), 8.72 (2H, d, J = 5.1 Hz) MS: 448 (M +
H)+, 446 (M - H)- 34 2-OCF3 ##STR00041## H N1: 0.55-3.30 (13H, m),
3.77 (1H, d, J = 16.5 Hz), 3.85 (1H, d, J = 16.5 Hz), 3.95-4.05
(1H, m), 5.84 (1H, s), 6.82 (1H, s), 6.83 (1H, s), 7.20-7.50 (4H,
m), 7.52 (1H, d, J = 3.3 Hz), 7.65 (1H, d, J = 3.3 Hz). MS: 505 (M
- H)-. 35 2-OCF3 ##STR00042## H N1: 0.50-3.40 (9H, m), 3.51-3.83
(2H, m), 3.94-4.18 (3H, m), 5.95 (1H, s), 6.74 (1H, s), 6.84-6.93
(2H, m), 7.22-7.55 (5H, m) MS: 490 (M - H)- 36 2-OCF3 ##STR00043##
H N1: 0.55-3.20 (13H, m), 3.78 (1H, d, J = 16.5 Hz), 3.86 (1H, d, J
= 16.5 Hz), 3.90-4.02 (1H, m), 5.86 (1H, s), 6.80 (1H, s), 6.83
(1H, s), 7.20-7.42 (4H, m), 7.93 (1H, s). MS: 489 (M - H)-. 37
2-OMe ##STR00044## H N1 (CD3OD): 0.90-3.26 (13H, m), 3.80-3.98 (5H,
m), 4.08 (1H, m), 6.04 (1H, s), 6.90-7.33 (6H, m). MS: 450 (M +
H)+. 38 2-OMe ##STR00045## H N1: 0.50-3.30 (13H, m), 3 75 (1H, d, J
= 16.5 Hz), 3.78 (3H, s), 3.82 (1H, d, J = 16.5 Hz), 3.90-4.05 (1H,
m), 5.84 (1H, s), 6.65 (1H, s), 6.70 (1H, s), 6.84-7.22 (4H, m),
7.23-8.50 (4H, m). MS: 445 (M - H)-. 39 2-Me ##STR00046## H N1:
0.50-3.40 (16H, m), 3.75-4.00 (3H, m), 5.75 (1H, s), 6.70 (1H, s),
6.78 (1H, s), 7.00-7.27 (4H, m), 7.31 (1H, t, J = 5.0 Hz), 8.69
(2H, d, J = 5.0 Hz) MS: 432 (M + H)+, 430 (M - H)-. 40 2-OCF3
##STR00047## H N1: 0.50-3.40 (13H, m), 3.75-4.10 (3H, m), 5.93 (1H,
s), 6.81 (1H, s), 6.83 (1H, s), 6.90-7.10 (3H, m), 7.30-7.48 (5H,
m), 8.70 (2H, d, J = 5.1 Hz) MS: 502 (M + H)+, 500 (M - H)-. 41
2-OEt ##STR00048## H N1: 0.50-3.40 (13H, m), 1.31 (3H, t),
3.73-4.18 (5H, m), 5.84 (1H, s), 6.68 (1H, s), 6.75 (1H, s), 6.89
(1H, t), 7.01 (2H, d), 7.08 (1H, s), 7.26 (1H, t), 7.96 (1H, s) MS:
451 (MH+), 449 (M - H)- 42 2-OEt ##STR00049## H N1: 0.50-3.25 (13H,
m), 1.22 (3H, t. J = 6.9 Hz), 3.75 (1H, d, J = 16.2 Hz), 3.82 (1H,
d, J = 16.2 Hz), 3.90-4.10 (3H, m), 5.80 (1H, s), 6.67 (1H, s),
6.72 (1H, s), 6.82-7.30 (4H, m), 7.53 (1H, d, J = 3.3 Hz), 7.66
(1H, d, J = 3.3 Hz). MS: 465 (M - H)-. 43 2-SMe ##STR00050## H N1:
0.50-3.40 (16H, m), 3.76-4.00 (3H, m), 5.70 (1H, brs), 6.75 (1H,
brs), 6.80 (1H, brs), 7.03-7.44 (5H, m), 7.96 (1H, s) MS: 453 (M +
H)+, 451(M - H)- 44 2-SMe ##STR00051## H N1: 0.50-3.40 (16H, m),
3.77 (1H, d, J = 16.7 Hz), 3.88 (1H, d, J = 16.7 Hz), 3.96 (1H, m),
5.69 (1H, brs), 6.73 (1H, brs), 6.79 (1H, brs), 7.02-7.42 (4H, m),
7.52-7.68 (2H, m) MS: 469 (M + H)+, 467 (M - H)- 45 2-OMe
##STR00052## H N1: 0.50-3.50 (13H, m), 3.70-4.00 (6H, m), 5.85 (1H,
s), 6.67 (1H, s), 6.75 (1H, s), 6.88-7.35 (4H, m), 7.85-7.90 (1H,
m) MS: 505 (M + H)+, 503 (M - H)- 46 2-OMe ##STR00053## Me MS:467
(M + H)+, N1: 0.45-3.30 (13H, m), 2.77 (3H, s), 3.81 (1H, d, J =
16.5 Hz), 3.85-4.00 (1H, m), 4.05 (1H, d, J = 16.5 Hz), 5.78 (1H,
s), 6.85-7.32 (4H, m), 7.03 (1H, s), 7.53 (1H, d, J = 3.3 Hz), 7.65
(1H, d, J = 3.3 Hz). 47 2-OCF.sub.3 ##STR00054## H MS: 501 (M +
H)+, N1: 0.50 (13H, m), 3.77 (1H, d, J = 16.5 Hz), 3.85 (1H, d, J =
16.5 Hz), 3.95-4.05 (1H, m), 5.87 (1H, s), 6.79 (1H, s), 6.81 (1H,
s), 7.14-8.48 (8H, m)
TABLE-US-00002 TABLE 1-2 ##STR00055## No. R R' D 48 ##STR00056##
##STR00057## MS: 479 (M + H)+, N1: 0.35-3.40 (13H, m), 3.76 (1H, d,
J = 16.2 Hz), 3.85 (1H, d, J = 16.2 Hz), 3.90-4.05 (1H, m), 5.94
(1H, s), 6.74 (1H, s), 6.81 (1H, s), 7.31 (1H, s), 7.35- 7.45 (2H,
m), 7.56 (1H, d, J = 3.3 Hz), 7.71 (1H, d, J = 3.3 Hz), 7.80-7.90
(1H, m), 7.94-8.02 (1H, m). 49 ##STR00058## ##STR00059## MS: 475 (M
+ H)+, N1: 0.60-3.40 (13H, m), 2.43 (3H, s), 3.71 (1H, d, J = 16.5
Hz), 3.77 (1H, d, J = 16.5 Hz), 3.90- 4.05 (1H, m), 5.76 (1H, s),
6.78 (1H, s), 6.84 (1H, s), 7.14 (1H, d, J = 5.4 Hz), 7.45 (1H, d,
J = 5.4 Hz), 7.52 (1H, d, J = 3.3 Hz), 7.65 (1H, d, J = 3.3 Hz). 50
##STR00060## ##STR00061## MS: 480 (M + H)+, N1: 0.40-3.30 (13H, m),
3.81 (1H, d, J = 16.2 Hz), 3.88 (1H, d, J = 16.2 Hz), 3.95-4.10
(1H, m), 6.44 (1H, s), 6.76 (1H, s), 6.79 (1H, s), 7.25 (1H, d, J =
7.2 Hz), 7.45 (1H, dd, J = 7.2, 7.2 Hz), 7.53 (1H, d, J = 3.3 Hz),
7.67 (1H, d, J = 3.3 Hz), 8.12 (1H, d, J = 7.2 Hz), 51 ##STR00062##
##STR00063## MS: 462 (M + H)+, N1: 0.30-3.40 (13H, m), 3.76 (1H, d,
J = 16.5 Hz), 3.86 (1H, d, J = 16.5 Hz), 3.90-4.04 (1H, m), 5.99
(1H, s), 6.41-7.34 (5H, m), 6.66 (1H, s), 6.74 (1H, s), 7.54 (lH,
d, J = 3.3 Hz), 7.69 (1H, d, J = 3.3 Hz), 11.14 (1H, s). 52
##STR00064## ##STR00065## MS: 462 (M + H)+, N1: 0.30-3.40 (13H, m),
3.77 (1H, d, J = 16.2 Hz), 3.89 (1H, d, J = 16.2 Hz), 3.95-4.10
(1H, m), 6.04 (1H, s), 6.46-7.54 (5H, m), 6.69 (1H, s), 6.78 (1H,
s), 7.58 (1H, d, J = 3.3 Hz), 7.75 (1H, d, J = 3.3 Hz), 10.60 (1H,
s). 53 ##STR00066## ##STR00067## MS: 474 (M + H)+, N1: 0.30-3.40
(13H, m), 3.80 (1H, d, J = 16.5 Hz), 3.88 (1H, d, J = 16.5 Hz),
4.00-4.15 (1H, m), 6.71 (1H, s), 6.74 (1H, s), 6.76 (1H, s),
7.48-8.85 (3H, m), 7.54 (1H, d, J = 3.3 Hz), 7.70 (1H, d, J = 3.3
Hz), 7.94 (1H, dd, J = 1.8, 7.8 Hz), 8.88 (1H, dd, J = 1.8, 8.4 Hz)
54 ##STR00068## ##STR00069## MS: 473 (M + H)+, N1: 0.30-3.40 (13H,
m), 3.78 (1H, d, J = 16.5 Hz), 3.84 (1H, d, J = 16.5 Hz), 3.91-4.05
(1H, m), 5.96 (1H, s), 6.72 (1H, s), 6.80 (1H, s), 7.15-7.46 (5H,
m), 7.62-8.04 (3H, m), 8.46-8.54 (1H, m) 55 ##STR00070##
##STR00071## MS: 473 (M + H)+, N1: 0.35-3.10 (13H, m), 3.81 (1H, d,
J = 16.5 Hz), 3.91 (1H, d, J = 16.5 Hz), 3.90-4.05 (1H, m), 5.90
(1H, s), 6.81 (1H, s), 6.84 (1H, s), 7.00-7.90 (8H, m), 8.45-8.50
(1H, m)
Example 56
(Process 1)
[0086] A hydrazine hydrate (0.96 mL, excess) was added to a
methanol solution (6.5 mL) of a compound (277 mg, 0.649 mmol) of
the following structural formula (XI) described in WO02/44180, and
stirred at 50.degree. C. for 26 hours. The solvent was removed
under reduced pressure to obtain a crude hydrazide. An acetic
anhydride (332 mg, 3.25 mmol) was added to a pyridine solution (6.5
mL) of the crude hydrazide at 0.degree. C. and stirred for 2 hours.
The solvent was removed under reduced pressure, and the residue was
treated with a silica gel column chromatography to obtain a Process
1 compound from fractions of methanol:methylene chloride (1:4).
[0087] 1H-NMR(300 MHz, DMSO-d6) .delta.=0.50-3.40(13H, m), 1.84(3H,
s), 3.72-3.90(5H, m), 3.96(1H, m), 5.82(1H, brs), 6.66(1H, brs),
6.73(1H, brs), 6.86-7.35(4H, m), 9.73(2H, brs)
[0088] MS(ESI) m/z 470(M+H)+, 468(M-H)-
##STR00072##
(Process 2)
[0089] A phosphorous oxychloride (0.13 mL, 1.40 mmol) was added to
a dioxane solution (14 mL) of the Process 1 compound (132 mg, 0.281
mmol), and stirred at 90.degree. C. for 1 hour. The reaction
solution was cooled down to 0.degree. C., an aqueous solution of 1N
sodium hydroxide was added thereto and neutralized. Then, the
reaction solution was extracted with an ethyl acetate. The organic
layer thereof was washed with a saturated saline solution, dried on
a magnesium sulfate, and the solvent thereof was removed under
reduced pressure. The solvent was removed under reduced pressure,
and the residue was purified with a thin layer silica gel column
chromatography (methanol:methylene chloride=1:5) to obtain a
compound 56 (32 mg, 25%).
Example 57
[0090] A compound 57 was obtained by the same method as that of
Example 56.
Example 58
[0091] A diphosphorus pentasulfide (204 mg, 0.922 mmol) was added
to a dioxane solution (7.4 mL) of the Process 1 compound (173 mg,
0.369 mmol) of Example 56, and stirred at 90.degree. C. for 3.5
hours. The reaction solution was cooled down to room temperature,
and the solvent was removed under reduced pressure. The residue was
purified with a thin layer silica gel column chromatography
(methanol:methylene chloride=1:5) to obtain a compound 58 (27 mg,
16%).
Example 59
[0092] A compound 59 was obtained by the same method as that of
Example 58.
Example 60
(Process 1)
[0093] A dichloromethane solution (2 mL) of a chloroacetic
anhydride (164 mg, 0.958 mmol) was added at 0.degree. C. to a
suspension consisting of a compound (200 mg, 0.639 mmol) of the
following structural formula (XII) described in WO02/44180,
dichloromethane (15 mL) and pyridine (0.15 mL, 1.92 mmol), and
stirred at room temperature for 15 hours. The reaction solution was
concentrated and azeotroped with toluene. Then, the solution was
dissolved in dichloromethane and washed with 0.1N hydrochloric acid
and a saturated saline solution, respectively. The organic layer
thereof was dried on an anhydrous sodium sulfate, concentrated, and
then purified with a silica gel column chromatography
(methanol:dichloromethane=1:19 to 1:3) to obtain a Process 1
compound (162 mg, 65%) as a white solid substance.
[0094] 1H-NMR(300 MHz, DMSO-d6) .delta.=0.50-3.40(9H, m), 3.59(1H,
d, J=12.9 Hz), 3.72(1H, d, J=12.9 Hz), 5.09(1H, d, J=10.8 Hz),
5.15(1H, d, J=10.8 Hz), 5.61(1H, brs), 6.68(1H, brs), 6.71(1H,
brs), 6.87-6.96(1H, m), 7.00-7.07(1H, m), 7.10-7.18(1H, m),
7.26-7.46(6H, m)
[0095] MS(ESI) m/z 466(MH+), 464(M-H)-
##STR00073##
(Process 2)
[0096] A potassium carbonate (88.0 mg, 0.640 mmol) was added to a
N,N-dimethylformamide solution (1 mL) of 2-hydroxypyridine (61.0
mg, 0.640 mmol), and stirred for 5 minutes. Then, the compound
(50.0 mg, 0.128 mmol) obtained in Process 1 was added thereto and
stirred at 90.degree. C. for 15 hours. The reaction solution was
separated with ethyl acetate-water, and extracted with
dichloromethane from the water layer thereof. The organic layer
thereof was combined together, washed with a saturated saline
solution, and then dried on an anhydrous sodium sulfate. The
residue obtained by concentration was purified with a thin layer
chromatography (methanol:ethyl acetate=1:4) to obtain a compound 60
(29.3 mg, 51%).
Examples 61 and 63
[0097] Compounds 61 and 63 were obtained by the same method as that
of Example 60.
Example 62
[0098] A compound 62 was synthesized in accordance with the method
described in WO02/44180.
Example 64
(Process 1)
[0099] A malonic monoethyl ester (361 mg, 2.73 mmol) and WSC/HCl
(393 mg, 2.05 mmol) were added to a N,N-dimethylformamide solution
(6.8 mL) of the compound (XII) (214 mg, 0.684 mmol) in Process 1 of
Example 60, and stirred at room temperature for 23 hours. After
removing the solvent under reduced pressure, the reaction solution
was separated with ethyl acetate-water. Then, the organic layer
thereof was washed with an aqueous solution of a saturated sodium
hydrogen carbonate and a saturated saline solution, respectively.
After being dried on an anhydrous magnesium sulfate, the solvent
was removed under reduced pressure to obtain a crude acyl compound
(a mixture with a diacyl compound).
[0100] A 28% ammonia water (7.5 mL) was added to an ethanol
solution (7.5 mL) of the crude acyl compound, and stirred at
50.degree. C. for 72 hours. After being cooled down to room
temperature, 6N--HCl was added and neutralized. Then, the solvent
was removed under reduced pressure. Methanol was added to the
residue, and insoluble substance was filtered out. The solvent was
removed under reduced pressure, and the residue was purified with a
silica gel column chromatography (methanol:methylene chloride=1:4)
to obtain a Process 1 compound (195 mg, 72%).
[0101] 1H-NMR(300 MHz, DMSO-d6) .delta.=0.50-3.60(11H, m), 3.73(1H,
d, J=16.7 Hz), 3.83(1H, d, J=16.7 Hz), 3.85(3H, s), 4.01(1H, m),
5.67(1H, br s), 6.86-7.57(8H, m)
[0102] MS(ESI) m/z 399(M+H).sup.+, 397(M-H).sup.-
(Process 2)
[0103] A diphosphorus pentasulfide (204 mg, 0.920 mmol) was added
to a 1,2-dimethoxyethane solution (12 mL) of the Process 1 compound
(183 mg, 0.460 mmol), and stirred at 50.degree. C. for 30 minutes.
After the solvent was removed under reduced pressure, the residue
was purified with a thin layer silica gel column chromatography
(methanol:methylene chloride=1:8) to obtain a Process 2 compound
(26 mg, 14%).
[0104] 1H-NMR(300 MHz, DMSO-d6) .delta.=0.50-3.40(9H, m), 3.72(1H,
d, J=15.8 Hz), 3.76(1H, d, J=14.9 Hz), 3.83(1H, d, J=14.9 Hz),
3.90(3H, s), 4.02(1H, m), 4.15(1H, d, 15.8 Hz), 5.67(1H, br s),
6.70(2H, d, J=11.7 Hz), 6.86-7.35(4H, m), 9.25(1H, br s), 9.56(1H,
br s)
[0105] MS(ESI) m/z 414(M+H).sup.+, 412(M-H).sup.-
(Process 3)
[0106] An aqueous solution of 40% chloroacetaldehyde (52 mg, 0.266
mmol) was added to a N,N-dimethylformamide solution (2 mL) of the
Process 2 compound (22 mg, 0.053 mmol), and stirred at 50.degree.
C. for 3 hours. After the reaction solution was cooled down to room
temperature, PS-TsNHNH2 (220 mg, 0.532 mmol) was added thereto and
stirred at room temperature for 3.5 hours. Then, a resin was
filtered out (and thoroughly washed with methylene chloride), and
the solvent was removed under reduced pressure. The residue was
purified with a thin layer silica gel column chromatography
(methanol:methylene chloride=1:10) to obtain a compound 64 (9 mg,
39%).
[0107] The structural formulae of Compounds 56 to 64 and data on
the compounds are shown in the following Table 2. In this regard,
the symbols in the Table are as follows: No.: Example No., R: a
substituent on a benzene ring, R': an acyl group, D: data on the
compound, MS:ESI-MS m/z, N1: 1H-NMR (DMSO-d6, TMS internal
standard, .delta.ppm). The number located in front of a substituent
in R indicates the position of the substituent on a benzene
ring.
TABLE-US-00003 TABLE 2 ##STR00074## No. R R' D 56 2-OMe
##STR00075## N1: 0.50-3.40 (13H, m), 2.43 (3H, s), 3.70-4.03 (6H,
m), 5.81 (1H, brs), 6.67 (1H, brs), 6.73 (1H, brs), 6.86-7.36 (4H,
m) MS: 452 (M + H)+, 450 (M - H)- 57 2-OCF3 ##STR00076## N1:
0.50-3.40 (13H, m), 2.41 (3H, s), 3.70-4.03 (3H, m), 5.83 (1H,
brs), 6.83 (2H, brs), 7.18-7.52 (4H, m) MS: 506 (M + H)+, 504 (M -
H)- 58 2-OMe ##STR00077## N1: 0.50-3.40 (13H, m), 2.66 (3H, s),
3.72 (3H, s), 3.75-3.88 (2H, m), 3.99 (1H, m), 5.80 (1H, brs), 6.70
(1H, brs), 6.74 (1H, brs), 6.82-7.39 (4H, m) MS: 468 (M + H)+, 466
(M - H)- 59 2-OCF3 ##STR00078## N1: 0.50-3.40 (13H, m), 2.50 (3H,
s), 3.70-4.12 (3H, m), 5.83 (1H, brs), 6.85 (2H, brs), 7.20-7.55
(4H, m) MS: 522 (M + H)+, 520 (M - H)- 60 2-OMe ##STR00079## N1:
0.50-3.40 (9H, m), 3.78 (1H, J = 16.0 Hz, d), 3.83 (1H, J = 16.0
Hz, d), 3.80-3.98 (1H, m), 3.95 (3H, s), 4.63 (1H, J = 15.6 Hz, d),
5.38 (1H, J = 15.6 Hz, d), 5.76 (1H, s), 6.10-6.40 (2H, m), 6.69
(1H, s), 6.76 (1H, s), 6.86-7.10 (3H, m), 7.27-7.52 (3H, m) MS: 449
(M + H)+ 61 2-OMe ##STR00080## N1: 0.50-3.40 (9H, m), 3.75 (1H, J =
16.0 Hz, d), 3.84 (1H, J = 16.0 Hz, d), 3.80-3.97 (1H, m), 3.95
(3H, s), 4.60 (1H, J = 15.3 Hz, d), 5.44 (1H, J = 15.3 Hz, d), 5.72
(1H, s), 6.40 (1H, J = 9.9 Hz, d), 6.69 (1H, s), 6.76 (1H, s),
6.86-7.37 (4H, m), 7.48 (1H, J = 15.3 & 3.0 Hz, dd), 7.82 (1H,
J = 3.0 Hz, d) MS: 483 (M + H)+ 62 2-OMe ##STR00081## N1: 0.50-3.40
(10H, m), 3.72 (1H, d, J = 16.5 Hz), 3.77 (3H, s), 3.81 (1H, d, J =
16.5 Hz), 3.90-4.05 (1H, m), 4.00-4.15 (2H, m), 5.69 (1H, s), 6.53
(1H, d, J = 6.9 Hz), 6.66 (1H, s), 6.71 (1H, s), 6.89 (1H, d, J =
6.6 Hz), 6.94-7.30 (4H, m), 7.64 (1H, d, J = 9.6 Hz), 8.40 (1H, s).
MS: 529 (M - H)-. 63 2-OMe ##STR00082## N1: 0.50-3.40 (9H, m), 3.71
(1H, J = 16.0 Hz, d), 3.81 (1H, J = 16.0 Hz, d), 3.87 (3H, s),
3.70-3.98 (1H, m), 4.94 (1H, J = 15.0 Hz, d), 5.15 (1H, J = 15.0
Hz, d), 5.73 (1H, s), 6.70 (1H, s), 6.76 (1H, s), 6.88-7.38 (6H,
m), 8.12-8.20 (2H, m) MS: 449 (M + H)+, 447 (M - H)- 64 2-OMe
##STR00083## N1: 0.50-3.40 (9H, m), 3.73 (1H, d, J = 16.2 Hz), 3.80
(1H, d, J = 16.2 Hz), 3.85 (3H, s), 4.01 (1H, m), 4.20 (1H, d, J =
16.8 Hz), 4.51 (1H, d, J = 16.8 Hz), 5.89 (1H, br s), 6.71 (2H, d,
J = 4.8 Hz), 6.86- 7.38 (4H, m), 7.64 (1H, d, J = 3.0 Hz), 7.70
(1H, d, J = 3.0 Hz) MS: 439 (M + H).sup.+, 437 (M - H).sup.-
Example 65
(Evaluation of the Sugar Transporting Capacity)
1. Preparation of Adipose Cells of Rats:
[0108] After the decapitation and venesection of 6 male Wistar rats
(body weight: 150 to 200 g), an incision was made in the abdomen of
each rat to extract 6 g in total of epididymal adipose tissues. The
tissues were finely cut into 2 mm.times.2 mm pieces in 6 ml of KRH
(Krebs-Ringer Hepes, composition: 130 mM of sodium chloride, 4.7 mM
of potassium chloride, 1.2 mM of potassium dihydrogenphosphate, 1.2
mM of magnesium sulfate, 1 mM of calcium chloride and 25 mM of
Hepes, pH=7.6) containing 5% of BSA (bovine serum albumin). 24 mg
of collagenase (type I) was added thereto and the digestion
treatment was conducted for about 40 minutes to obtain about 6 ml
of isolated adipose cells. The collagenase was removed by the
buffer exchange. 2% BSA/KRH solution was added to the residue for
the re-suspension to obtain 45 ml of an adipose cell
suspension.
2. Evaluation of the Sugar Transporting Capacity:
[0109] The sugar transporting capacity of the compound of the
present invention was evaluated with reference to a method
described in a literature [Annual Review of Biochemistry, Vol. 55,
p. 1059 (1986)]. In the test, 200 .mu.L of the adipose cell
suspension was poured in each polystyrene test tube, 100 .mu.L of
the solution of the test substance (by dilution of 10 mg/mL
dimethyl sulfoxide solution with KRH) was added thereto, and the
obtained mixture was shaken and then cultured at 37.degree. C. for
30 minutes.
[0110] The sugar transporting capacity was evaluated by measuring
the quantity of 2-[.sup.14C(U)]-deoxy-D-glucose incorporated per a
unit time. Namely, 2-[.sup.14C(U)]-deoxy-D-glucose was added to the
adipose cell suspension after the pre-culture (the final
concentration: 0.5 .mu.Ci/sample). 5 minutes later, cytochalasin B
(final concentration: 10 .mu.M) was added to the mixture to
terminate the sugar transportation. After forming a dinonyl
phthalate layer, the obtained mixture was centrifuged to separate
the adipose cells from the buffer. The quantity of
2-[.sup.14C(U)]-deoxy-D-glucose contained in the adipose cell layer
was determined with a liquid scintillation counter to determine the
quantity of the incorporated sugar. In this evaluation system, when
insulin (100 nM) having the effect of increasing the
sugar-transporting capacity was used, the effect was about 7 times
as high as that obtained in the insulin-free control group.
[0111] The results of the evaluation of the sugar-transporting
capacity obtained by using the compounds of the present invention
are shown in Table 3. The sugar-transporting capacity in Table 3
was determined in terms of the concentration (EC.sub.50: .mu.g/mL)
of a test compound, having a reinforcing effect corresponding to
50% on the basis of the reinforcing effect of insulin (100 nM).
(The symbols in Table 3 are as follows: No: Example No., and A:
sugar-transporting capacity.)
TABLE-US-00004 TABLE 3 No. A 14 0.0060 20 0.064 22 0.090 25 0.020
27 0.050 33 0.10 34 0.070 38 0.021 41 0.10 42 0.060 43 0.070 44
0.060 46 0.040 52 0.040 55 0.0040
* * * * *